147 Vickery PJ, Wheeler JL, Mulcahy C (1987) Factors affecting the hydrogen cyanide potential of white clover (Trifolium repens L.). Aust. J. Agric. Res. 38:1053-1059. Webber JJ, Roycroft CR, Callinan JD (1985) Cyanide poisoning of goats from sugar gums (Eucalyptus cladocalyx). Aust. Vet. J. 62:28. Winks WR (1940) Qd. Agric. J. 54:364-366. Cardiac glycosides Core data Common sources: • Important Plants Nerium oleander (oleander) Cascabela thevetia [=Thevetia peruviana] (yellow oleander) Cryptostegia grandiflora (rubber vine) Bryophyllum spp. (mother-of-millions) Homeria spp. (cape tulips) Adonis microcarpa (pheasant’s eye) Digitalis purpurea (foxglove) Corchorus olitorius (jute) • Pharmaceuticals Digoxin Animals affected: cattle, horses Poisoning circumstances: • garden clippings (oleanders, foxglove) • in hay or seeds in feed grain (cape tulips, pheasant’s eye, jute) • hunger or lack of other feed (mother-of-millions) • overdose of digoxin Main effects: • sudden death • cardiac arrhythmia • diarrhoea with blood • azotaemia • focal myocardial necrosis Diagnosis: • access • cardiac arrhythmia • myocardial histopathology Therapy: • activated charcoal + electrolyte replacement fluid PO • + atropine • + propranolol Syndrome names: Two syndromes are associated with intoxication by cardiac glycosides: • acute cardiac glycoside poisoning – discussed in this section • cotyledonosis or krimpsiekte [Afrikaans = “twisted disease”] due to certain bufadienolides in particular plants and confined to southern Africa – discussed in the following separate section Chemical structure: A cardiac glycoside is any plant-derived steroid glycoside with cardiotonic activity. This activity depends on the presence in the aglycone of an unsaturated lactone ring and a hydroxyl group in a specific spatial relationship. Some 400 such compounds have been identified. [adapted from Lewis’ Dictionary of Toxicology 1998]. There are some structural affinities with cucurbitacins (q.v.) and some similarities of pathological effect. 148 Cardiac glycosides consist of a steroidal aglycone linked to a sugar or sugars. There are two groups of cardiac glycosides, cardenolides with 23-carbon aglycones (5 member lactone ring) and bufadienolides with 24-carbon aglycones (6 member lactone ring). Sources: Human & veterinary medicaments (cardiac inotropic agents) based on cardenolides derived from Digitalis spp. plants, e.g. digoxin (Lanoxin), or from Strophanthus spp. plants, e.g. proscillaridin (Talusin) Cardioactive steroids of Bufo spp. toads (q.v.) have close affinities with cardiac glycosides Plants in Australia known or suspected to contain cardiac glycosides Toxicity & toxin types are indicated by data in square brackets, thus [*=poisoning reported; toxin type: B=bufadienolide, C=cardenolide, unlabelled=unknown] Family Apocynaceae (native and naturalised plants in Australia are reviewed by Forster & Williams 1996) *Nerium oleander (oleander)[*C] [DM131] *Cascabela thevetia (L.) Lippold [=Thevetia peruviana (Pers.) K.Schum.] (yellow oleander)[*C] [DM132] *Acokanthera oblongifolia (bushman's poison, winter sweet)[C] *Allamanda cathartica (yellow allamanda) *Allamanda neriifolia Carissa ovata (currant bush, blackberry, burrum bush, conkberry) [C] Cerbera manghas (sea mango)[C] Cerbera odollan [C] *Plumeria rubra (frangipani) 149 Nerium oleander (oleander flowers and seed pods [RAM Photo] 150 Cascabela thevetia (yellow oleander) [RAM Photos] 151 Family Asclepiadaceae (native and naturalised plants in Australia are reviewed by Forster & Liddle 1996) *Cryptostegia grandiflora (rubber vine)[*C] [DM116] (Marohasy & Forster 1991); listed as a Weed of National Significance for Australia; toxicity (McGavin 1969) *Cryptostegia madagascariensis [C] (Marohasy & Forster 1991) *Araujia sericiflora [= A. hortorum] (white moth plant)[*] *Asclepias curassavica (red cotton)[*C] [DM103] *Gomphocarpus physocarpus (balloon cotton)[*] [DM104] (Bailey & White 1916) *Gomphocarpus fruticosus (balloon cotton)[*C] *Calotropis procera (calotrope, rubber bush, kapok tree, king’s crown, cabbage tree)[C] Cryptostegia grandiflora (rubber vine) flowers and seed pod [RAM Photo] 152 Family Celastraceae *Euonymus europaeus (spindle)[C] Family Crassulaceae *Bryophyllum daigremontianum x B. delagoense (hybrid mother-of-millions)[*B] [DM84] *Bryophyllum delagoense [=B. tubiflorum] (mother-of-millions)[*B] [DM85] *Bryophyllum pinnatum (live-leaf, resurrection plant)[*B] *Bryophyllum daigremontianum [B] *Bryophyllum fedtschenkoi [B] *Bryophyllum proliferum [B] *Bryophyllum beauverdii [a climber, naturalised in a few small localities around Brisbane] *Cotyledon orbiculata (pig's ears)[B] *Crassula spathulata [*] Bryophyllum delagoense [ RAM Photo] 153 Bryophyllum daigremontianum x B. delagoense hybrid (left); Bryophyllum pinnatum (right) [RAM Photos] Family Iridaceae (native and naturalised plants in Australia are reviewed by Cooke 1986) *Homeria flaccida (breyniana) (one-leaf cape tulip)[*B] *Homeria miniata (two-leaf cape tulip)[*B] *Diplarrena moraea (butterfly flag)[*B] *Gynandriris setifolia [B] *Iris foetidissima (stinking iris) *Iris germanica *Iris pseudacorus (yellow flag) *Moraea aristata [B] *Moraea bellendenii [B] *Moraea vegeta [B] Sisyrinchium iridifolium (blue pigroot)[B] Sisyrinchium sp.A (micranthum) (scour weed)[*B] 154 Homeria flaccida (one-leaf cape tulip) [left]; Homeria miniata (two-leaf cape tulip) [right] [RAM Photos] Family Liliaceae *Convalaria majalis (lily-of-the-valley)[C] *Ornithogalum thyrsoides (chinkerinchee, star of Bethlehem) [* ] (Hall 1953, Forshaw 1999) Family Melianthaceae *Melianthus comosus (cape honey flower)[B] (Anderson & Koekemoer 1969) *Melianthus major (tall cape honey flower)[B] Family Moraceae Antiaris toxicaria Leschen. var. macrophylla (R.Br.) Corner (umpas tree) [C] - distributed in Top End Northern Territory and Cape York Peninsula Qld. as 155 well as in south-east Asia; the latex is toxic if injected, but less toxic by ingestion (Chew 1989). Family Ranunculaceae *Adonis microcarpa [= Adonis annua] (pheasant's eye)[*C – convallatoxin, convalloside] *Helleborus niger (Christmas rose)[B] Family Scrophulariaceae *Digitalis purpurea (foxglove)[C] Digitalis purpurea (foxglove) inflorescence [RAM Photo] Family Tiliaceae *Corchorus olitorius (jute)[*C – seeds contain strophanthidin (Soliman & Saleh 1950, Hamaguchi et al. 1998) and olitoriside (Turakhozhaev et al. 1970); young leaves used as human food in Egypt and Japan (Azuma et al. 1999)] 156 Corchorus olitorius (jute) flowering plant and seeds [Brock Photo (left); RAM Image (right)] _____________________________________________________________________________________ Major plants containing cardiac glycosides overseas (number of toxic species per genus given in parenthesis) Southern Africa (Kellerman et al. 1988) Family Apocynaceae - Acokanthera spp.(2), Adenium multiflorum, Nerium spp.(2), Strophanthus spp.(3), Thevetia peruviana Family Asclepiadaceae - Cryptostegia spp.(2) Family Crassulaceae (plakkies) - Cotyledon orbiculata, Tylecodon spp.(3), Kalanchöe spp.(5) [K. lanceolata – Masvingwe & Mavenyengwa 1997] Family Iridaceae (tulp) - Homeria spp.(3), Moraea spp.(3) Family Liliaceae (slangkop [Afrikaans, = snake’s head]) - Urginea spp.(6), Ornithoglossum viride, Lidneria clavata, Scilla natalensis, Bowiea volubilis, Ornithogalum nanodes (Bamhare 1998), Ornithogalum umbellatum Family Melianthaceae - Melianthus spp.(2), Bersama abyssinica [B – hellibrigenin 3- acetate (Kupchan 1969)] Family Santalaceae - Thesium spp.(2) Northern America Family Asclepiadaceae - Asclepias spp.(9) Family Apocynaceae - Nerium oleander (Galey et al. 1998) Europe Family Apocynaceae - Nerium oleander (native of the Mediterranean region) Asia Family Moraceae – Antiaris toxicaria (umpas tree) [C – convallatoxin, convalloside] _____________________________________________________________________________________ 157 Toxicity: There are 2 forms of cardiac glycoside poisoning - acute (described here) and cotyledonosis (only in southern Africa & described separately below) Ruminants, pigs, horses, dogs and humans are susceptible. Birds are relatively resistant. Plants retain toxicity when dried Toxic doses (for example): • Horse lethal dose of Nerium oleander leaf for adults = 15-30 g (10-20 leaves) • Cattle LD50 Bryophyllum delagoense (tubiflorum) flower heads = 7 g wet weight/kg; leaf & stem = 40 g wet weight/kg (McKenzie & Dunster 1986) Radunz et al. (1984) demonstrated lack of toxicity for cattle and sheep from Calotropis procera of Northern Territory origin. Reports from Queensland are that cattle can eat the plant without ill effect in the dry season, but if they are stressed (e.g. mustered) they may die suddenly (Anon 2001). Australian records of cardiac glycoside toxicity: Horses: Nerium oleander (Hughes et al. 2002); Cryptostegia grandiflora (Cook et al. 1990) Cattle: Nerium oleander (RA McKenzie, unpublished data 1994, 1995); Corchorus olitorius (McKenzie et al. 1992); Bryophyllum spp. (McKenzie & Dunster 1986, 1987; McKenzie et al. 1987, 1989); Cryptostegia grandiflora (McGavin 1969); Homeria spp. Pigs: Adonis microcarpa (Davies & Whyte 1989) Mode of action: Cardiac glycosides inhibit cardiac Na+-K+-ATPase, the sodium pump. The binding site on the enzyme molecule for cardiac glycosides or their aglycones is in the extracellular portion of the α- subunit (Kaplan 2002). This enzyme is involved in the maintenance of membrane potential of cardiac muscle fibres and in the active transport of Na and K ions across the cell